DC exosome therapy to resolve inflammatory bone loss and oral infection

DC外泌体疗法解决炎症性骨质流失和口腔感染

基本信息

批准号：
10450633
负责人：
CHRISTOPHER William CUTLER
金额：
$ 36.21万
依托单位：
AUGUSTA UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-14 至 2026-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10450633
关键词：
Alveolar Bone Loss Anti-Inflammatory Agents Antigen Presentation Antigens Autoimmune Diseases Autologous Dendritic Cells Biodistribution C-Type Lectins CD4 Positive T Lymphocytes CD86 gene Cell Maturation Cells Chronic Communication Custom Data Degenerative Disorder Dendritic Cells Development Diagnostic Disease Endocytosis Experimental Models Future Gingiva Goals Histopathology Human Immune Immune response Immunobiology Immunotherapy In Situ In Vitro Inflammation Inflammatory Inflammatory Response Injections Interleukin-10 Lesion MADH2 gene Malignant Neoplasms Mediating Microbe Molecular Morbidity - disease rate Mouth Diseases Multivesicular Body Mus Oral Organ Pathogenesis Pathologic Pathology Pathway interactions Patients Periodontitis Periodontium Peripheral Phase I/II Clinical Trial Phenotype Plasma Proteins Proteomics Publishing Regulatory T-Lymphocyte Reporting Risk Role STAT3 gene Safety Saliva Salivary Secondary to Signal Transduction Site System T-Lymphocyte Testing Therapeutic Tissues Transforming Growth Factor beta adaptive immune response base bone bone preservation cancer biomarkers cytokine exosome immune function improved outcome in vivo inflammatory bone loss mortality mouse model nanoparticle nanosized novel novel strategies novel therapeutic intervention oral infection pathogen premature preservation prevent prototype receptor receptor binding response secondary lymphoid organ uptake

项目摘要

Project Abstract Periodontitis (PD) is a bone degenerative inflammatory disease that contributes to increased risk of other diseases with more serious mortality and morbidity profiles. We propose here a novel immune therapeutic strategy for PD, using cellular nano-particles, exosomes (EXO) from dendritic cells. Dendritic cells are the “directors” of the adaptive immune response, as such, their immune functions can be exploited to treat chronic immune-mediated diseases such as cancer and autoimmune diseases. This is first study to our knowledge to employ phenotypically stable exosomes from dendritic cells to treat experimental PD in mice. Our strategy consists of “reprograming” immune cells in the periodontium responsible for destructive inflammatory bone loss using custom DC exo. Our tactic is to inject DC exo directly into the gingiva, to target anti-inflammatory pathways in specific immune cells, to prevent/resolve alveolar bone loss. The overall objective of these studies to acquire a better understanding of the immunobiology of DC-derived exo in vivo and in vitro in the murine model of experimental PD, and relate these findings to exo isolated from humans with PD. Our aims are to test the hypotheses that: Aim 1. Exogenous DCexo delivered to the PD lesion persist in situ and reprogram recipient DCs and T cells involved in experimental PD in mice in vivo; Aim 2. DC exo preserve molecular cargo and reprogram acceptor DCs and T cells through receptor binding and endocytosis; Aim 3. Endogenous exo from humans with PD contain molecular cargo of direct relevance to exo therapy and PD pathogenesis. Future goals include: 1. the development of DC exo therapy for PD in humans, 2. assessment of salivary exo molecular cargo for diagnostic potential in PD and other oral diseases

项目摘要牙周炎 (PD) 是一种骨退行性炎症性疾病，会增加其他疾病的风险我们在此提出一种新型免疫疗法。 PD 的策略是使用细胞纳米颗粒，来自树突状细胞的外泌体 (EXO)。适应性免疫反应的“指挥者”，因此，他们的免疫功能可用于治疗慢性病据我们所知，这是首次针对癌症和自身免疫性疾病等免疫介导的疾病进行研究。使用来自树突状细胞的表型稳定的外泌体来治疗小鼠实验性 PD。由牙周组织中的“重新编程”免疫细胞组成，导致破坏性炎症性骨质流失使用定制的 DC exo 我们的策略是将 DC exo 直接注射到牙龈中，以靶向抗炎途径。这些研究的总体目标是在特定的免疫细胞中预防/解决牙槽骨丢失。更好地了解 DC 衍生的 exo 在小鼠模型体内和体外的免疫生物学实验性帕金森病，并将这些发现与从帕金森病患者身上分离出来的外泌体联系起来。假设：目标 1. 递送至 PD 病变的外源 DCexo 持续存在原位并重新编程接受者 DC 和 T 细胞参与小鼠体内实验性 PD；目的 2. DC 外切细胞保存分子货物并通过受体结合和内吞作用重新编程受体 DC 和 T 细胞；目标 3. 内源性外泌体；患有 PD 的人类含有与外切疗法和 PD 发病机制直接相关的分子货物。包括：1.人类PD DC exo疗法的开发，2.唾液exo分子货物的评估具有诊断帕金森病和其他口腔疾病的潜力